Complement and Graft-versus-host Disease

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Clinical haematology and BMT unit,Necker Hospital, Paris
Clinical haematology and BMT unit,Saint Antoine Hospital, Paris
Clinical haematology and BMT unit,Saint Louis Hospital,Paris
European Georges Pompidou Hospital
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier:
NCT01520623
First received: December 26, 2011
Last updated: November 16, 2012
Last verified: November 2012
  Purpose

Allogeneic haematopoietic stem cell transplantation (HSCT) often remains the only curative treatment for haematological malignancies. The anti-leukaemic effect of allogeneic HSCT, called the GvL (Graf-versus-Leukemia) effect, is often associated to the development of an immune response against healthy recipient cells leading to a graft-versus-host disease (GvHD) in 20 to 70% of allogeneic HSCT. Acute GvHD, that usually targets the skin, the gastrointestinal (GI) tract and the liver, is an important cause of morbidity and mortality after allogeneic HSCT, particularly in the case of GI GvHD. The main goal of the research in the field of allogeneic HSCT is to determine strategies that could decrease the risk of GvHD without affecting the GvL effect. According to GVHD experimental models, it is likely that GvL but not GvHD may occur in the absence of inflammatory signals induced by the transplant-associated conditioning. Based on this hypothesis, we have chosen to analyse the role of Complement system in patients who received allogeneic HSCT. Indeed, Complement system is a major actor of inflammation and in the generation of tissue destruction, both of which are involved in the physiopathology of GVHD. Furthermore, it might be a potential target of some available inhibitory drugs (purified C1-Inhibitor, anti-C5 antibodies) in a preventive or curative manner in such patients. Preliminary data obtained from 34 allografted patients in our institution suggest that Complement activation by the classical pathway is correlated to the occurrence of GI GVHD. The goal of our current project, in order to confirm these preliminary results in a larger series, is to explore Complement system activation in patients who received allogeneic HSCT in three Adult Hematology departments in Paris fot two years and to correlate the biological results to the clinical events occurring after HSCT.


Condition Intervention
Allografted With Myeloablative Conditioning
Other: Serum concentration /Serum inflammatory

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Prevention
Official Title: Role of Complement System in Human Allogeneic Haematopoietic Stem Cell Transplantation

Resource links provided by NLM:


Further study details as provided by Assistance Publique - Hôpitaux de Paris:

Primary Outcome Measures:
  • Activation of the complement system and the development of acute gut GvHD [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    Assessment of the activation of the complement system after human allogeneic stem cell transplantation and of its potential correlation with the development of acute gut GvHD


Secondary Outcome Measures:
  • Overall survival [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
    Overall Survival at 3, 6, 9 , 12 and 24-month Post HCST

  • Overall survival without relapse [ Time Frame: 2 Years ] [ Designated as safety issue: Yes ]
    Relapse


Estimated Enrollment: 69
Study Start Date: April 2010
Estimated Study Completion Date: July 2013
Estimated Primary Completion Date: February 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Allografted patients
Allografted patients with myeloablative conditioning for an haematological malignancy. Patients will be followed for at least 12 months after transplantation and blood samples drawn before conditioning and once a week for 12 weeks after transplantation to analyze the serum concentration of Complement factors (C3, C4, B factor), Complement regulatory proteins (C1-inhibitor, I and H Factors) and analysis of the surface expression of Complement regulatory molecules such as CD46, CD55 and CD59 and the serum inflammatory cytokine levels
Other: Serum concentration /Serum inflammatory
Allografted patients with myeloablative conditioning for an haematological malignancy. Patients will be followed for at least 12 months after transplantation and blood samples drawn before conditioning and once a week for 12 weeks after transplantation to analyze the serum concentration of Complement factors (C3, C4, B factor), Complement regulatory proteins (C1-inhibitor, I and H Factors) and analysis of the surface expression of Complement regulatory molecules such as CD46, CD55 and CD59 and the serum inflammatory cytokine levels
Other Name: Serum concentration /Serum inflammatory

Detailed Description:

The study will be performed in allografted patients with myeloablative conditioning for an haematological malignancy from 3 adult transplant units.

Patients will be followed for at least12 months after transplantation and blood samples drawn before conditioning and once a week for 12 weeks after transplantation to analyze:

  • serum concentration of Complement factors (C3, C4, B factor), Complement regulatory proteins (C1-inhibitor, I and H Factors) and analysis of the surface expression of Complement regulatory molecules such as CD46, CD55 and CD59.
  • serum inflammatory cytokine levels

In addition, patients with clinical signs of gut GVHD will be explored by gastrointestinal endoscopy to perform gut biopsies. C5b9 deposure will be then analyzed by immunohistochemistry on GVHD lesions.

Activation of complement system will be defined by a decrease of complement factor levels of 50% and values under lower physiological limits. The clinical evolution and the inflammatory cytokine profile of patients with such an activation profile will be compared to that of those without complement activation.

A data base containing biological and clinical data will be established. Biological results will be correlated to post-transplant clinical events, in particular the occurrence of gut GVHD but also non relapse mortality and overall survival by adapted statistical tests (comparison of percentages by Chi-2 of Pearson, comparison of survival curves by logrank, multivariate analysis by logistic regression test or cox model).

The number of required patients will be established by comparison of the percentage of gut GVHD in the patients with or without complement activation. Based on our preliminary results, we hypothesize that 2/3 patients will not have complement activation among whose 20% will develop acute gut GVHD. We expect an increase of acute gut GVHD up to 60% of the patients with complement activation that would represent 1/3 of the cohort.

With a bilateral alpha risk of 5% and a power of 80%, the number of required patients is 23 in the activated group and 46 in the non activated group, thus a total of 69 patients.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Allografted patients with myeloablative conditioning for an haematological malignancy
  • Age > 18 years old and < 65 years.
  • The patient must have access to social insurance according to local regulations.
  • Patient must give a written informed consent (personally signed and dated) before completing any study related procedure

Exclusion Criteria:

  • Age < 18 years old and > 65 years
  • Patient with active infection HIV, HTLV1, Hepatite B ou C
  • Uncontrolled infection(s), (i.e. documented bacterial, parasitical, or fungal infection).
  • Patient with lupus
  • Patient with transaminases > 5N, TP<30% with Facteur V < 30% before allogreffe
  • Creatinine clearance < 50ml/min
  • Absence of any psychological condition potentially hampering signing informed consent
  • Patient refused to sign informed consent
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01520623

Locations
France
Saint Antoine Hospital
Paris, France, 75012
Necker Hospital
Paris, France, 75
Saint Louis Hospital
Paris, France, 75010
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Clinical haematology and BMT unit,Necker Hospital, Paris
Clinical haematology and BMT unit,Saint Antoine Hospital, Paris
Clinical haematology and BMT unit,Saint Louis Hospital,Paris
European Georges Pompidou Hospital
Investigators
Principal Investigator: Marie-Thérèse RUBIO, MD, PhD Saint Antoine Hospital
  More Information

No publications provided

Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT01520623     History of Changes
Other Study ID Numbers: CRC 08025
Study First Received: December 26, 2011
Last Updated: November 16, 2012
Health Authority: France: Ministry of Health

Keywords provided by Assistance Publique - Hôpitaux de Paris:
Allogeneic haematopoietic stem cell transplantation (HSCT)
Myeloablative conditioning for an haematological malignancy
Graft-versus-host disease (GvHD)
Activation of complement system
Gut GVHD

Additional relevant MeSH terms:
Graft vs Host Disease
Immune System Diseases
Complement System Proteins
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on September 22, 2014